This application claims the benefit of foreign priority under 35 U.S.C. xc2xa7119 to German patent application no. 19947457.5, filed on Oct. 2, 1999, the contents of which are incorporated by reference herein.
The invention relates to compounds of the formula I, 
in which R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30) and R(31) have the meanings indicated below, their preparation and their use, in particular in pharmaceuticals.
The compounds of the formula I according to the invention were hitherto unknown. They act on the so-called Kv1.5 potassium channel and inhibit a potassium current described as xe2x80x9cultra-rapidly activating delayed rectifierxe2x80x9d in the human atrium. The compounds are therefore very particularly suitable as novel antiarrhythmic active compounds, in particular for the treatment and prophylaxis of atrial arrhythmias, e.g. atrial fibrillation (AF) or atrial flutter.
The compounds can be used for the termination of existing atrial fibrillation or flutter to restore sinus rhythm (cardioversion). Furthermore the compounds reduce the incidence for the development of new episodes of fibrillation (maintenance of sinus rhythm, prophylaxis).
Atrial fibrillation (AF) and atrial flutter are the most frequent persistent cardiac arrhythmias. The occurrence increases with increasing age and frequently leads to fatal sequelae, such as, for example, cerebral apoplexy. AF affects about 1 million Americans annually and leads to more than 80,000 strokes each year in the USA. The presently customary antiarrhythmics of classes I and III, reduce the reoccurrence rate of AF, but because of their potential proarrhythmic side effects only have restricted use. There is therefore a great medical need for the development of better medicaments for the treatment of atrial arrhythmias (S. Nattel, Am. Heart J. 130, 1995, 1094-1106; xe2x80x9cNewer developments in the management of atrial fibrillationxe2x80x9d).
It was shown that most supraventricular arrhythmias are subject to so-called xe2x80x9creentryxe2x80x9d excitatory waves. Such reentries occur when the cardiac tissue has a slow conductivity and at the same time very short refractory periods. The increasing of the myocardial refractory time by prolongation of the action potential is a recognized mechanism for ending arrhythmias or preventing their formation (T. J. Colatsky et al., Drug Dev. Res. 19, 1990, 129-140; xe2x80x9cPotassium channels as targets for antiarrhythmic drug actionxe2x80x9d). The length of the action potential is essentially determined by the extent of repolarizing K+ currents which flow out of the cell via various K+ channels. Particularly great importance is ascribed here to the so-called xe2x80x9cdelayed rectifierxe2x80x9d IK, which consists of 3 different components: IKr, IKs and IKur.
Most known class III antiarrhythmics (e.g. dofetilide, E4031 and d-sotalol) mainly or exclusively block the rapidly activating potassium channel IKr, which can be detected both in cells of the human ventricle and in the atrium. However, it has been shown that at low or normal heart rates these compounds have an increased proarrhythmic risk, arrhythmias which are described as xe2x80x9cTorsades de pointesxe2x80x9d being observed in particular (D. M. Roden, Am. J. Cardiol. 72, 1993, 44B-49B; xe2x80x9cCurrent status of class III antiarrhythmic drug therapyxe2x80x9d). In addition to this high, in some cases fatal, risk at low frequency, a decrease in the efficacy under the conditions of tachycardia, in which the action is especially needed, has been found for the IKr blockers (xe2x80x9cnegative use-dependencexe2x80x9d).
While some of these disadvantages can possibly be overcome by blockers of the slowly activating components (IKs), their efficacy has hitherto not been confirmed, as no clinical investigations with IKs channel blockers are known.
The xe2x80x9cparticularly rapidlyxe2x80x9d activating and very slowly inactivating component of the delayed rectifier IKur (=ultra-rapidly activating delayed rectifier), which corresponds to the Kv1.5 channel, plays a particularly large role in the repolarization period in the human atrium. In comparison to the inhibition of IKr or IKs, inhibition of the IKur potassium outward current is thus a particularly effective method for the prolongation of the atrial action potential and thus for the ending or prevention of atrial arrhythmias. Mathematical models of the human action potential suggest that the positive effect of a blockade of the IKur, especially under the pathological conditions of chronic atrial fibrillation, should be particularly pronounced (M. Courtemanche, R. J. Ramirez, S. Nattel, Cardiovascular Research 1999, 42, 477-489: xe2x80x9cIonic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical modelxe2x80x9d).
In contrast to IKr and IKs, which also occur in the human ventricle, the IKur admittedly plays an important role in the human atrium, but not in the ventricle. For this reason, on inhibition of the IKur current in contrast to the blockade of IKr or IKs, the risk of a proarrhythmic action on the ventricle is excluded from the start (Z. Wang et al., Circ. Res. 73, 1993, 1061-1076: xe2x80x9cSustained Depolarisation-Induced Outward Current in Human Atrial Myocytesxe2x80x9d; G. -R. Li et al, Circ. Res. 78, 1996, 689-696: xe2x80x9cEvidence for Two Components of Delayed Rectifier K+ Current in Human Ventricular Myocytesxe2x80x9d; G. J. Amos et al., J. Physiol. 491, 1996, 31-50: xe2x80x9cDifferences between outward currents of human atrial and subepicardial ventricular myocytesxe2x80x9d).
Antiarrhythmics which act via a selective blockade of the IKur current or Kv1.5 channel were previously not available, however, on the market. For numerous pharmaceutical active compounds (e.g. tedisamil, bupivacaine or sertindole), a blocking action on the Kv1.5 channel was admittedly described, but the Kv1.5 blockade here in each case represents only a side effect next to other principal actions of the substances.
WO 98 04 521 claims aminoindans as potassium channel blockers which block the Kv1.5 channel. The applications WO 98 18 475 and WO 98 18 476 claim the use of various pyridazinones and phosphine oxides as antiarrhythmics, which should act via a blockade of the IKur. However, the same compounds were originally also described as immuno-suppressants (WO 96 25 936). The compounds described in these mentioned applications are structurally completely different to the compounds according to the invention of this application.
It has now surprisingly been found that the 2xe2x80x2-substituted 1,1xe2x80x2-biphenyl-2-carboxamides described here are potent blockers of the human Kv1.5 channel. They can therefore be used as novel antiarrhythmics having a particularly advantageous safety profile. In particular, the compounds are suitable for the treatment of supraventricular arrhythmias, e.g. atrial fibrillation or atrial flutter.
The compounds according to the invention were previously unknown. Some structurally related compounds are described in Helv. Chim. Acta 1994 (70) 70 and references cited there. For the peptide compounds described there (e.g. compound A), however, no potassium channel-blocking activity is known. Moreover, compounds of this type should have too low a metabolic stability for use as antiarrhythmics on account of the numerous peptide bonds. 
A further similar compound (compound B) is mentioned in European Patent Application EP 0620216. The compound B and all other compounds of this application carry, in the position of R(3), a specific substituent (e.g. benzoyl-1,2,3,4-tetrahydroisoquinoline), which is not included in the compounds according to the invention of this application. The compounds mentioned in EP 0 620 216 act as vasopressin antagonists and thus have a completely different biological activity to the blockers of the Kv1.5 channel described here. 
The present invention relates to compounds of the formula I 
in which:
R(1) is C(O)OR(9), SO2R(10), COR(11), C(O)NR(12)R(13) or C(S)NR(12)R(13);
R(9) is CxH2xxe2x80x94R(14);
x is 0, 1, 2, 3 or 4,
where x cannot be 0 if R(14) is OR(15) or SO2Me;
R(14) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3, OCF3, C2F5, C3F7, CH2F, CHF2, OR(15), SO2Me, phenyl, naphthyl, biphenylyl, furyl, thienyl or an N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, biphenylyl, furyl, thienyl and the N-containing hetero-aromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, OCF3, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3 or phenyl which is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(10), R(11) and R(12)
independently of one another are defined as R(9);
R(13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF3;
R(2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF3;
R(3) is CyH2yxe2x80x94R(16);
y is 0, 1, 2, 3 or 4,
where y cannot be 0 if R(16) is OR(17) or SO2Me;
R(16) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3, C2F5, C3F7, CH2F, CHF2, OR(17), SO2Me, phenyl, naphthyl, furyl, thienyl or an N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3- or 4-pyridyl,
where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
or
R(3) is CHR(18)R(19);
R(18) is hydrogen or CzH2zxe2x80x94R(16), where R(16) is defined as indicated above;
z is 0, 1, 2 or 3;
R(19) is COOH, CONH2, CONR(20)R(21), COOR(22), CH2OH;
R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, CvH2vxe2x80x94CF3 or CwH2w-phenyl,
where the phenyl ring is unsubstituted or substituted by 1, 2 or 3 substitutents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v is 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3;
or
R(3) and R(4)
together are a chain of 4 or 5 methylene groups, of which one methylene group can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(methyl)- or xe2x80x94N(benzyl)-;
R(5), R(6), R(7) and R(8)
independently of one another are hydrogen, F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R(30) and R(31)
independently of one another hydrogen or alkyl having 1, 2 or 3 carbon atoms;
or
R(30) and R(31)
together form a chain of 2 methylene groups;
and their pharmaceutically acceptable salts.
Preferred compounds of the formula I are those in which:
R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);
R(9) is CxH2xxe2x80x94R(14);
x is 0, 1, 2, 3 or 4,
where x cannot be 0 if R(14) is OR(15);
R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, C2F5, OR(15), phenyl, furyl, thienyl or an N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3 or phenyl,
which is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, NO2, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(10), R(11) and R(12)
independently of one another are defined as R(9);
R(13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF3;
R(2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF3;
R(3) is CyH2yxe2x80x94R(16);
y is 0, 1, 2, 3 or 4,
where y cannot be 0 if R(16) is OR(17);
R(16) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, C2F5, OR(17), phenyl, furyl, thienyl or an N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where phenyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(17) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3-, or 4-pyridyl,
where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
or
R(3) is CHR(18)R(19);
R(18) is hydrogen or CzH2zxe2x80x94R(16), where R(16) is defined as indicated above;
z is 0, 1, 2 or 3;
R(19) is CONH2, CONR(20)R(21), COOR(22), CH2OH;
R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, CvH2vxe2x80x94CF3 or CwH2w-phenyl,
where the phenyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v is 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3;
R(5), R(6), R(7) and R(8)
independently of one another are hydrogen, F, Cl, Br, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R(30) and R(31)
independently of one another hydrogen or alkyl having 1, 2 or 3 carbon atoms;
or
R(30) and R(31)
together form a chain of 2 methylene groups;
and their pharmaceutically acceptable salts.
Particularly preferred compounds of the formula I are those in which:
R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);
R(9) is CxH2xxe2x80x94R(14);
x is 0, 1, 2, 3 or 4,
where x cannot be 0 if R(14) is OR(15);
R(14) is cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(15), phenyl, furyl, thienyl or an N-containing heteroaromatic having 3, 4 or 5 carbon atoms,
where phenyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(15) is alkyl having 1 or 2 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3 or phenyl,
which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(10), R(11) and R(12)
independently of one another are defined as R(9);
R(13) is hydrogen;
R(2) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R(3) is CHR(18)R(19);
R(18) is hydrogen or CzH2zxe2x80x94R(16);
z is 0, 1, 2 or 3;
R(19) is CONH2, CONR(20)R(21), COOR(22) or CH2OH;
R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, CvH2vxe2x80x94CF3 or CwH2w-phenyl,
where the phenyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v is 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(17), phenyl, furyl, thienyl or an N-containing heteroaromatic having 3, 4 or 5 carbon atoms,
where phenyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1 or 2 substitutents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(17) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3- or 4-pyridyl,
where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(4) is hydrogen or alkyl having 1 or 2 carbon atoms;
R(5), R(6), R(7) and R(8)
independently of one another are hydrogen, F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R(30) and R(31)
independently of one another hydrogen or methyl;
or
R(30) and R(31)
together form a chain of 2 methylene groups;
and their pharmaceutically acceptable salts.
Particularly preferred compounds of the formula I are also those in which:
R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);
R(9) is CxH2xxe2x80x94R(14);
x is 0, 1, 2, 3 or 4,
where x cannot be 0 if R(14) is OR(15);
R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(15), phenyl, furyl, thienyl or an N-containing heteroaromatic having 3, 4 or 5 carbon atoms,
where phenyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(15) is alkyl having 1 or 2 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3 or phenyl,
which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(10), R(11) and R(12)
independently of one another are defined as R(9);
R(13) is hydrogen;
R(2) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R(3) is CyH2yxe2x80x94R(16);
y is 0, 1, 2, 3 or 4,
where y cannot be 0 if R(16) is OR(17);
R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(17), phenyl, furyl, thienyl or an N-containing heteroaromatic having 3, 4 or 5 carbon atoms,
where phenyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(17) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3- or 4-pyridyl,
where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(4) is hydrogen or alkyl having 1 or 2 carbon atoms;
R(5), R(6), R(7) and R(8)
independently of one another are hydrogen, F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R(30) and R(31)
independently of one another hydrogen or methyl;
or
R(30) and R(31)
together form a chain of 2 methylene groups;
and their pharmaceutically acceptable salts.
Very particularly preferred compounds of the formula I are those in which:
R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);
R(9) is CxH2xxe2x80x94R(14);
x is 0, 1, 2 or 3;
R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, phenyl or pyridyl,
where phenyl and pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, OH, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(10), R(11) and R(12)
independently of one another are defined as R(9);
R(13) is hydrogen;
R(2) is hydrogen;
R(3) is CyH2yxe2x80x94R(16);
y is 0, 1 or 2;
R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, CF3, phenyl or pyridyl,
where phenyl and pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, OH, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(4) is hydrogen;
R(5), R(6), R(7) and R(8)
independently of one another are hydrogen, F, CF3, CN, COOMe, CONH2, NH2, OH, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms;
R(30) and R(31)
independently of one another hydrogen or methyl;
or
R(30) and R(31)
together form a chain of 2 methylene groups;
and their pharmaceutically acceptable salts.
Especially preferred compounds of the formula I are those in which:
R(1) is C(O)OR(9) or COR(11);
R(9) is CxH2xxe2x80x94R(14);
x is 0, 1, 2 or 3;
R(14) is cycloalkyl having 5 or 6 carbon atoms or phenyl,
where phenyl is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(11) is defined as R(9);
R(2) is hydrogen;
R(3) is CyH2yxe2x80x94R(16);
y is 0, 1 or 2;
R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, CF3, phenyl or pyridyl
where phenyl and pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(4) is hydrogen;
R(5), R(6), R(7) and R(8)
independently of one another are hydrogen, F, CF3, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms;
R(30) and R(31)
are hydrogen;
and their pharmaceutically acceptable salts.
Alkyl radicals and alkylene radicals can be straight-chain or branched. This also applies to the alkylene radicals of the formulae CxH2x, CyH2y, CzH2z, CvH2v and CwH2w. Alkyl radicals and alkylene radicals can also be straight-chain or branched if they are substituted or are contained in other radicals, e.g. in an alkoxy radical or in a fluorinated alkyl radical. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethyl-butyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl. The divalent radicals derived from these radicals, e.g. methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene, 1,1-butylene, 1,4-butylene, 1,5-pentylene, 2,2-dimethyl-1,3-propylene, 1,6-hexylene, etc., are examples of alkylene radicals.
Cycloalkyl radicals can likewise be branched. Examples of cycloalkyl radicals having 3 to 11 carbon atoms are cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2-methylcyclobutyl, 3-methylcyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, menthyl, cycloheptyl, cyclooctyl etc.
N-containing heteroaromatics having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are considered in particular as 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. The corresponding N-oxides of these compounds are furthermore included, i.e., for example, 1-oxy-2-, -3- or -4-pyridyl.
The N-containing heterocycles pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl are particularly preferred. Pyridyl is either 2-, 3- or 4-pyridyl. Thienyl is either 2- or 3-thienyl. Furyl is either 2- or 3-furyl.
Monosubstituted phenyl radicals can be substituted in the 2, 3 or 4 position, disubstituted in the 2,3, 2,4, 2,5, 2,6, 3,4 or 3,5 position, or trisubstituted in the 2,3,4, 2,3,5, 2,3,6, 2,4,5, 2,4,6 or 3,4,5 position. The same correspondingly also applies analogously to the N-containing hetero-aromatics, the thiophene or the furyl radical.
If a radical is di- or trisubstituted, the substituents can be identical or different.
If R(3) and R(4) are together a chain of 4 or 5 methylene groups, of which one methylene group can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 etc., then these radicals together with the nitrogen atom of the compound of the formula I form a 5- or 6-membered nitrogen heterocycle, such as, for example, pyrrolidine, piperidine, morpholine, thiomorpholine etc.
If the compounds of the formula I contain one or more acidic or basic groups or one or more basic heterocycles, the invention also includes the corresponding physiologically or toxicologically tolerable salts, in particular the pharmaceutically utilizable salts. Thus the compounds of the formula I which carry acidic groups, e.g. one or more COOH groups, for example as alkali metal salts, preferably sodium or potassium salts, or as alkaline earth metal salts, e.g. calcium or magnesium salts, or as ammonium salts, e.g. as salts with ammonia or organic amines or amino acids, can be used. Compounds of the formula I which carry one or more basic, i.e. protonatable, groups or contain one or more basic heterocyclic rings can also be used in the form of their physiologically tolerable acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates etc. If the compounds of the formula I simultaneously contain acidic and basic groups in the molecule, the invention also includes internal salts, so-called betaines, in addition to the salt forms described. Salts can be obtained from the compounds of the formula I according to customary processes, for example by combination with an acid or base in a solvent or dispersant or alternatively from other salts by anion exchange.
If they are appropriately substituted, the compounds of the formula I can be present in stereoisomeric forms. If the compounds of the formula I contain one or more asymmetric centers, these independently of one another can have the S configuration or the R configuration. The invention includes all possible stereoisomers, e.g. enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, e.g. enantiomers and/or diastereomers, in any desired ratios. The invention thus includes enantiomers, for example, in enantiomerically pure form, both as levo- and as dextrorotatory antipodes, and also in the form of mixtures of the two enantiomers in different ratios or in the form of racemates. If desired, the individual stereoisomers can be prepared by resolution of a mixture according to customary methods or, for example, by stereoselective synthesis. If mobile hydrogen atoms are present, the present invention also comprises all tautomeric forms of the compounds of the formula I.
The compounds of the formula I can be prepared by different chemical processes, which are likewise included in the present invention. Some typical routes are outlined in the reaction sequences designated below as schemes 1, 2, 3 and 4. The radicals R(1) to R(8) used here are in each case defined as indicated above, if not stated otherwise below.
Thus a compound of the formula I according to scheme 1 is obtained, for example, starting from diphenic anhydride derivatives of the formula II as precursors which are commercially obtainable or known from the literature. Reduction of the compounds II using sodium borohydride followed by reaction with potassium phthalimide as described in Tetrahedron 45 (1989) 1365-1376 yields the biphenylcarboxylic acids of the formula IV. By coupling with amines of the formula HNR(3)R(4) followed by hydrazinolysis of the phthalimide, the aminomethyl compounds of the formula VI are obtained, from which, by reaction with suitable derivatives of the formula R(1)-X, the compounds of the formula I according to the invention are obtained in which R(2) is hydrogen and R(1), R(3), R(4), R(5), R(6), R(7) and R(8) have the meanings indicated above. Subsequent alkylation using suitable alkylating agents of the formula R(2)Y, in which Y is a nucleofugic leaving group, e.g. Cl, Br or I, yields the corresponding compounds of the formula I in which R(2) is alkyl having 1 to 4 carbon atoms.
Alternatively, the biphenylcarboxylic acids of the formula IV can also be converted by hydrazinolysis to the aminocarboxylic acids of the formula VII which are then converted by reaction of the amino group with compounds of the formulae R(1)-X and R(2)-Y followed by amidation of the carboxylic acids with amines of the formula HNR(3)R(4) to give compounds of the formula I according to the invention (scheme 2).
In some cases, it can be useful to first prepare compounds of the formula la (scheme 3) in which R(9) is an easily removable radical, such as, for example, tert-butyl or benzyl, by one of the previously mentioned methods. After removal of the corresponding protective group, e.g. with trifluoroacetic acid for the Boc group or by catalytic hydrogenation for the benzyloxy-carbonyl radical, the compounds of the formula IX are obtained, which can then in turn be converted into other compounds of the formula I according to the invention by reaction with compounds of the formula R(1)-X.
Another possibility for the preparation of compounds of the formula la consists in the palladium-catalyzed coupling of a phenyl bromide or iodide of the formula X with a phenylboronic acid of the formula XI (Suzuki coupling; scheme 4), which can be carried out, for example, in the presence of Pd[(PPh)3]4 as a catalyst, sodium carbonate as a base and 1,2-dimethoxyethane as a solvent. The compounds of the formula la can then be converted into other compounds of the formula I according to the invention as described above and in scheme 3.
The necessary boronic acids XI can be obtained from the compounds XII, in which Z represents hydrogen, bromine or iodine, by ortholithiation respectively metal-halogen exchange and subsequent reaction with boric acid trimethylate.
The abovementioned reactions of the compounds of the formulae VI, VII and IX with compounds of the formula R(1)-X correspond to the known conversion of an amine to a carboxamide, sulfonamide, carbamate, urea or thiourea derivative. The radical X here is a suitable nucleofugic leaving group, such as, for example, F, Cl, Br, imidazole, O-succinimide etc.
For the preparation of compounds of the formula I or VIII in which R(1) is C(O)OR(9), i.e. carbamates, compounds of the formula R(1)-X, for example, are used in which X is chlorine or O-succinimide, i.e. chloroformates or succinimidocarbonates.
For the preparation of compounds of the formula I or VIII in which R(1) is SO2R(10), i.e. sulfonamides, as a rule compounds of the formula R(1)-X are used in which X is chlorine, i.e. sulfonyl chlorides.
For the preparation of compounds of the formula I or VIII in which R(1) is COR(11), i.e. carboxamides, compounds of the formula R(1)-X, for example, are used in which X is chlorine, imidazole or acetoxy, i.e. carbonyl chlorides, carboxylic acid imidazolides or mixed anhydrides. However, the free acids of the formula R(1)-OH can also be used in the presence of suitable condensing agents such as carbodiimides or uronium salts such as TOTU.
For the preparation of compounds of the formula I or VIII in which R(1) is CONR(12)R(13) or C(S)NR(12)R(13), i.e. ureas or thioureas, instead of the compounds of the formula R(1)-X it is also possible to use compounds of the formula R(12)N(xe2x95x90Cxe2x95x90O), or R(12)N(xe2x95x90Cxe2x95x90S), i.e. isocyanates or isothiocyanates.
The abovementioned reactions of the compounds of the formula IV or VIII with amines of the formula HNR(3)R(4) correspond to the known conversion of a carboxylic acid to a carboxamide. Numerous methods have been described in the literature for carrying out these reactions. They can be carried out particularly advantageously by activation of the carboxylic acid, e.g. with dicyclohexylcarbodiimide (DCC), if appropriate with addition of hydroxybenzotriazole (HOBT) or dimethylaminopyridine (DMAP), or with O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU). However, reactive acid derivatives can also be synthesized first according to known methods, e.g. acid chlorides by reaction of the carboxylic acids of the formula IV or VIII with inorganic acid halides, such as, for example, SOCl2, or acid imidazolides by reaction with carbonyldiimidazole, which are then reacted with the amines of the formula HNR(3)R(4), if appropriate with the addition of an auxiliary base.
In all procedures, it may be appropriate to temporarily protect functional groups in the molecule in certain reaction steps. Such protective group techniques are familiar to the person skilled in the art. The choice of a protective group for groups under consideration and the processes for their introduction and removal are described in the literature and can if necessary be adapted to the individual case without difficulties. 
The compounds of the formula I according to the invention and their physiologically tolerable salts can thus be used in animals, preferably in mammals, and in particular in humans, as pharmaceuticals on their own, in mixtures with one another or in the form of pharmaceutical preparations. The present invention also relates to the compounds of the formula I and their physiologically tolerable salts for use as pharmaceuticals, their use in the therapy and prophylaxis of the syndromes mentioned and their use for the production of medicaments therefor and of medicaments having K+ channel-blocking action. The present invention furthermore relates to pharmaceutical preparations which, as active constituent, contain an efficacious dose of at least one compound of the formula I and/or of a physiologically tolerable salt thereof in addition to customary, pharmaceutically innocuous vehicles and excipients. The pharmaceutical preparations normally contain 0.1 to 90% by weight of the compounds of the formula I and/or their physiologically tolerable salts. The pharmaceutical preparations can be prepared in a manner known per se. To this end, the compounds of the formula I and/or their physiologically tolerable salts are brought, together with one or more solid or liquid pharmaceutical vehicles and/or excipients and, if desired, in combination with other pharmaceutical active compounds, into a suitable administration form or dose form, which can then be used as a pharmaceutical in human medicine or veterinary medicine.
Pharmaceuticals which contain compounds of the formula I according to the invention and/or their physiologically tolerable salts can be administered orally, parenterally, e.g. intravenously, rectally, by inhalation or topically, the preferred administration being dependent on the individual case, e.g. the particular form of the disease to be treated.
The person skilled in the art is familiar on the basis of his/her expert knowledge with which excipients are suitable for the desired pharmaceutical formulation. In addition to solvents, gel-forming agents, suppository bases, tablet excipients and other active compound carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, agents for achieving a depot effect, buffer substances or colorants.
For the obtainment of an advantageous therapeutic action, the compounds of the formula I can also be combined with other pharmaceutical active compounds. Thus in the treatment of cardiovascular diseases advantageous combinations with substances having cardiovascular activity are possible. Possible combination partners of this type which are advantageous for cardiovascular disorders are, for example, other antiarrhythmics, i.e. class I, class II or class III antiarrhythmics, such as, for example, IKs or IKr channel blockers, e.g. dofetilide, or furthermore hypotensive substances such as ACE inhibitors (for example enalapril, captopril, ramipril), angiotensin antagonists, K+ channel activators, and also alpha- and beta-receptor blockers, but also sympathomimetic compounds and compounds having adrenergic activity, as well as Na+/H+ exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other substances having a positive inotropic action, such as, for example, digitalis glycosides, or diuretics.
For an oral administration form, the active compounds are mixed with the additives suitable therefor, such as vehicles, stabilizers or inert diluents, and brought by the customary methods into the suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Inert carriers which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular cornstarch. In this case, preparation can be carried out both as dry and as moist granules. Suitable oily vehicles or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod-liver oil. Suitable solvents for aqueous or alcoholic solutions are, for example, water, ethanol or sugar solutions or mixtures thereof. Further excipients, also for other administration forms, are, for example, polyethylene glycols and polypropylene glycols.
For subcutaneous or intravenous administration, the active compounds, if desired with the substances customary therefor such as solubilizers, emulsifiers or further excipients, are brought into solution, suspension or emulsion. The compounds of the formula I and their physiologically tolerable salts can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned.
Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compounds of the formula I or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of such solvents. If required, the formulation can also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and a propellant. Such a preparation contains the active compound customarily in a concentration of approximately 0.1 to 10, in particular of approximately 0.3 to 3, percent by weight.
The dose of the active compound of the formula I or of the physiologically tolerable salts thereof to be administered depends on the individual case and is to be adjusted to the conditions of the individual case as customary for an optimum action. Thus it depends, of course, on the frequency of administration and on the potency and duration of action of the compounds in each case employed for therapy or prophylaxis, but also on the nature and severity of the illness to be treated and on sex, age, weight and individual responsiveness of the human or animal to be treated and on whether treatment is acute or prophylactic. Customarily, the daily dose of a compound of the formula I on administration to a patient weighing approximately 75 kg is 0.001 mg/kg of body weight to 100 mg/kg of body weight, preferably 0.01 mg/kg of body weight to 20 mg/kg of body weight. The dose can be administered in the form of an individual dose or can be divided into two or more, e.g. 2, 3 or 4, individual doses. In particular in the treatment of acute cases of cardiac arrhythmias, for example in an intensive care unit, parenteral administration by injection or infusion, e.g. by an intravenous continuous infusion, can also be advantageous.
Experimental Section
List of Abbreviations
CDI Carbonyldiimidazole
DIC Diisopropylcarbodiimide
DMAP 4-Dimethylaminopyridine
DMF N,N-Dimethylformamide
EDAC N-Ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide hydrochloride
EA Ethyl acetate
m.p. Melting point (if not stated otherwise the melting points of the unpurified crude products are stated; the melting points of the respective pure substances can definitely be markedly higher)
HOBT 1-Hydroxy-1H-benzotriazole
in vac. In vacuo
S Solvent
Me Methyl
RT Room temperature
THF Tetrahydrofuran
TOTU O-[(Cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyl-uronium tetrafluoroborate
Precursor 1: 7H-Dibenzo[c,e]oxepin-5-one
9.0 g (0.24 mol) of sodium borohydride were added in portions at 5xc2x0 C. in the course of 10 min to a suspension of 50.0 g (0.22 mol) of diphenic anhydride in 220 ml of DMF. After stirring at RT for 1 h, the reaction mixture was poured onto 220 ml of 6 M hydrochloric acid, diluted with 750 ml of water and stirred for 2 h. The deposited precipitate was filtered off with suction and 35.0 g of 7H-dibenzo[c,e]oxepin-5-one were obtained; m.p. 131xc2x0 C.
Precursor 2: 2xe2x80x2-Phthalimidomethylbiphenyl-2-carboxylic Acid
A mixture of 35 g (0.17 mol) of 7H-dibenzo[c,e]oxepin-5-one and 30.8 g (0.17 mol) of potassium phthalimide in 330 ml of DMF was heated at 170xc2x0 C. for 18 h. After cooling, the deposited precipitate was filtered off with suction and introduced into 160 ml of glacial acetic acid. After stirring for 1 h, the mixture was diluted with 650 ml of ice water and the deposited product was filtered off with suction and dried in vacuo. 44.8 g of 2xe2x80x2-phthalimidomethylbiphenyl-2-carboxylic acid were obtained; m.p. 198xc2x0 C.
Precursor 3: 2xe2x80x2-Aminomethylbiphenyl-2-carboxylic Acid
A suspension of 10.0 g (28 mmol) of 2xe2x80x2-phthalimidomethylbiphenyl-2-carboxylic acid in 450 ml of methanol was treated with 20 ml of hydrazine hydrate and heated at 40xc2x0 C. for 1.5 h. The reaction mixture was concentrated and the residue was taken up in 250 ml of methylene chloride. After filtering off undissolved 2,3-dihydrophthalazine-1,4-dione, the mother liquor was concentrated and 4.8 g of 2xe2x80x2-aminomethylbiphenyl-2-carboxylic acid were obtained.
General Procedure for the Synthesis of Mixed Succinimidocarbonates from Alcohols (precursors 4a-4k)
5.0 g (19.5 mmol) of disuccinimidyl carbonate are added in portions at 0xc2x0 C. to a solution of 19.5 mmol of the appropriate alcohol and 1.2 g (9.8 mmol) of DMAP in 30 ml of methylene chloride and 30 ml of acetonitrile. After stirring at RT for 2.5 to 10 h, 25 ml of water are added and the organic phase is washed a further 2 times with water. After drying and concentration, the corresponding succinimidocarbonates are obtained, usually as crystalline solids.
Precursor 4a:
According to the general procedure, 3.2 g of 4-fluorobenzyl N-succinimido-carbonate were obtained; m.p. 89xc2x0 C. (ether).
Precursor 4b:
From 11.7 mmol of 4-trifluoromethylbenzyl alcohol, corresponding to the general procedure 2.3 g of 4-trifluoromethylbenzyl N-succinimido-carbonate were obtained; m.p. 102xc2x0 C. (ether).
Precursor 4c:
From 10.5 mmol of xcex1-methyl-4-(trifluoromethyl)benzyl alcohol, corresponding to the general procedure 1.6 g of xcex1-methyl-4-(trifluoromethyl)benzyl N-succinimidocarbonate were obtained; m.p. 115xc2x0 C. (ether).
Precursor 4d:
From 19.5 mmol of 4,4,4-trifluorobutanol, corresponding to the general procedure 4.0 g of 4,4,4-trifluorobutyl N-succinimidocarbonate were obtained; m.p. 72xc2x0 C. (ether).
Precursor 4e:
From 26.3 mmol of xcex1-methyl-3-(trifluoromethyl)benzyl alcohol, corresponding to the general procedure 5.1 g of xcex1-methyl-3-(trifluoromethyl)benzyl N-succinimidocarbonate were obtained; m.p. 77xc2x0 C. (ether).
Precursor 4f:
From 31.6 mmol of xcex1-methyl-2,6-difluorobenzyl alcohol, corresponding to the general procedure 1.6 g of xcex1-methyl-2,6-difluorobenzyl N-succinimido-carbonate were obtained; m.p. 108xc2x0 C. (ether).
Precursor 4g:
From 25 mmol of xcex1-methyl-2-(trifluoromethyl)benzyl alcohol, corresponding to the general procedure 3.5 g of xcex1-methyl-2-(trifluoromethyl)benzyl N-succinimidocarbonate were obtained.
Precursor 4h:
From 25 mmol of (S)-1-phenylethanol, corresponding to the general procedure 3.5 g of (S)-xcex1-methylbenzyl N-succinimidocarbonate were obtained.
Precursor 4i:
From 25 mmol of (R)-1-phenylethanol, corresponding to the general procedure 3.5 g of (R)-xcex1-methylbenzyl N-succinimidocarbonate were obtained.
Precursor 4j:
From 25 mmol of xcex1-methyl-4-fluorobenzyl alcohol, corresponding to the general procedure 4.3 g of xcex1-methyl-4-fluorobenzyl N-succinimido-carbonate were obtained.
Precursor 4k:
From 9.8 mmol of (S)-1-phenyl-1-butanol, corresponding to the general procedure 1.7 g of (S)-xcex1-propylbenzyl N-succinimidocarbonate were obtained.
Precursor 5a: 2xe2x80x2-Aminomethylbiphenyl-2-carboxylic Acid Phenethylamide
From 2xe2x80x2-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), after activation with CDI and reaction with phenethylamine, 2xe2x80x2-phthalimido-methylbiphenyl-2-carboxylic acid phenethylamide was obtained; m.p. 156xc2x0 C.
5.0 g (10.9 mmol) of the product were dissolved in 200 ml of methanol and treated with 5 ml of hydrazine hydrate. After stirring at 40xc2x0 C. for 1 h, the reaction mixture was concentrated and the residue was taken up in methylene chloride. After filtering off the 2,3-dihydrophthalazine-1,4-dione formed, the mother liquor was concentrated and the residue was purified by flash chromatography using methylene chloride/methanol 20:1. 3 g of 2xe2x80x2-aminomethylbiphenyl-2-carboxylic acid phenethylamide were obtained.
Precursor 5b: 2xe2x80x2-Aminomethylbiphenyl-2-carboxylic Acid Benzylamide
From 2xe2x80x2-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), after conversion into the acid chloride using thionyl chloride and reaction with benzylamine, 2xe2x80x2-phthalimidomethylbiphenyl-2-carboxylic acid benzylamide was obtained. 1.2 g (2.7 mmol) of the product were dissolved in 55 ml of methanol and treated with 1.35 ml of hydrazine hydrate. After stirring at 40xc2x0 C. for 1 h, the reaction mixture was concentrated and the residue was taken up in methylene chloride. After filtering off the 2,3-dihydro-phthalazine-1,4-dione formed, the mother liquor was concentrated and the residue was purified by flash chromatography using methylene chloride/methanol 30:1. 0.49 g of 2xe2x80x2-aminomethylbiphenyl-2-carboxylic acid benzylamide was obtained.
Precursor 5c: 2xe2x80x2-Aminomethylbiphenyl-2-carboxylic Acid Isopentylamide
From 3 g (8.4 mmol) of 2xe2x80x2-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), by reaction with isopentylamine in the presence of HOBT and DIC, 3.2 g of 2xe2x80x2-phthalimidomethylbiphenyl-2-carboxylic acid isopentylamide were obtained; m.p. 169xc2x0 C. The product was dissolved in 100 ml of methanol and treated with 5 ml of hydrazine hydrate. After stirring at 40xc2x0 C. for 1 h, the cooled reaction mixture was filtered. The filtrate was concentrated and the residue was taken up in methylene chloride. After washing with water, drying and concentrating, 1.8 g of 2xe2x80x2-amino-methylbiphenyl-2-carboxylic acid isopentylamide were obtained.
Precursor 5d: 2xe2x80x2-Aminomethylbiphenyl-2-carboxylic Acid 2-(2-pyridyl)ethyl-amide
From 10 g (28 mmol) of 2xe2x80x2-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), by reaction with 2-(2-pyridyl)ethylamine in the presence of HOBT and DIC, 13 g of 2xe2x80x2-phthalimidomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained; m.p. 155xc2x0 C. The product was suspended in 300 ml of methanol and treated with 20 ml of hydrazine hydrate. After stirring at 40xc2x0 C. for 1 h, the cooled reaction mixture was filtered. The filtrate was concentrated and the residue was taken up in EA. The product was extracted into the aqueous phase 2 times using 2 M hydrochloric acid. The aqueous phase was then rendered alkaline with potassium carbonate and extracted 2 times with EA. After washing with water, drying and concentrating, 7.3 g of 2xe2x80x2-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained.
Precursor 6: 2xe2x80x2-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic Acid
500 mg (2 mmol) of benzyl N-succinimidocarbonate dissolved in 2.5 ml of dioxane were added dropwise at 0xc2x0 C. to a solution of 455 mg (2 mmol) of 2xe2x80x2-aminomethylbiphenyl-2-carboxylic acid (precursor 3) and 336 mg (4 mmol) of sodium hydrogencarbonate in 5 ml of dioxane and 5 ml of water. After stirring at RT for 4 h, the mixture was concentrated in vacuo, diluted with water, acidified and extracted with ethyl acetate. 590 mg of 2xe2x80x2-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid were obtained.
Precursor 7: 2xe2x80x2-(tert-Butoxycarbonylaminomethyl)biphenyl-2-carboxylic Acid
65 ml of 1 M sodium hydroxide solution were added to a solution of 12.0 g (53 mmol) of 2xe2x80x2-aminomethylbiphenyl-2-carboxylic acid (precursor 3) in 130 ml of 1,4-dioxane and 65 ml of water and, after complete dissolution, 12.6 g (58 mmol) of di-tert-butyl dicarbonate were added. After stirring at RT for 2 h, the mixture was concentrated in vacuo, diluted with water and extracted 2 times with methylene chloride. The aqueous phase was acidified with 1 M potassium hydrogensulfate solution and extracted with ethyl acetate. After extensive concentration, addition of n-heptane and allowing to stand overnight, the product precipitated and 7.6 g of 2xe2x80x2-(tert-butoxycarbonylaminomethyl)biphenyl-2-carboxylic acid were obtained; m.p. 136xc2x0 C.
General Procedure for the Removal of the Boc Protective Group:
The n-Boc-protected aminomethylbiphenyl derivative (1 g to 10 ml of solution) was added to a solution of trifluoroacetic acid in dichloromethane (30% strength). The mixture was stirred at room temperature for 30 minutes and the solvent was then removed in vacuo on a rotary evaporator. The residue was taken up in ethyl acetate and washed with saturated sodium hydrogencarbonate solution. The organic phase was dried over magnesium sulfate, the solvent was removed in vacuo and the corresponding 2xe2x80x2-aminomethylbiphenyl-2-carboxamides were obtained.
Precursor 8a: 2xe2x80x2-Aminomethylbiphenyl-2-carboxylic Acid (2,4-difluoro-benzyl)amide
The compound was obtained from the Boc-protected compound (Example 8c) according to the general procedure. Alternatively, the compound can also be isolated directly as the trifluoroacetate and reacted further.
Further Precursors 8:
The corresponding amines were analogously liberated from the Boc-protected compounds of Examples 8d-8o and 10a-10o.
General Procedure for the Reaction of Aminomethylbiphenyls with Succinimidocarbonates to Give Carbamates (Examples 1a to 1u)
0.45 mmol of the respective succinimidocarbonate dissolved in 2 ml of dioxane is slowly added dropwise to a solution of 0.45 mmol of the respective 2xe2x80x2-aminomethylbiphenyl and 38 mg (0.45 mmol) of sodium hydrogencarbonate in 2 ml of dioxane and 2 ml of water. The mixture is stirred at RT for 2 to 12 h, concentrated, diluted with water and extracted with EA, and the organic phase is washed with water. After drying and concentration, the corresponding carbamates are obtained.